IL-18 is a proinflammatory cytokine that belongs to the IL-1 family of ligands. Okamura et al., 1995, Nature 378:88-91. Also referred to as IFN-γ-inducing factor, IL-18 is a cytokine that plays an important role in the TH1 response, primarily by its ability to induce IFN-γ production in T cells and natural killer cells. IL-18 is related to the IL-1 family in both structure and function. In terms of structure, IL-18 and IL-1β share significant primary amino acid sequences and are both folded as β-sheet polypeptides. In terms of function, IL-18 induces gene expression and synthesis of IL-1, TNF, Fas ligand, and several cytokines.
The activity of IL-18 is transduced through a signal transducing pathway initiated by its forming of a IL-18 receptor (IL-18R) complex. The IL-18R includes a binding chain termed α-IL-18 receptor (α-IL-18R), a member of the IL-1R family previously identified as the IL-1R-related protein (IL-1Rrp), and a β-IL-18 receptor (β-IL-18R), also a member of the IL-1R family and previously identified as AcPL; both chains are required for signaling. Born et al., 1998, J. Biol. Chem. 273:29445-50. The IL-18/IL-18R complex recruits IL-1R-activating kinase and TNF receptor-associated factor-6, which phosphorylates nuclear factor kappaB (NFkappaB)-inducing kinase with subsequent activation of NFkappaB. IL-18 participates in both innate and acquired immunity. Dinarello, 1999, J. Allergy Clin. Immun. 103:11-24.
Increased levels of IL-18 and/or involvement of IL-18 mediated signals in pathogenesis have been demonstrated in a variety of human disease states, including autoimmune diseases (WO2004/002519; WO2005/063290; WO2004/034988; Mallet et al., 2002, Circ. Res. 91:441-448), hepatic diseases (Finitto et al., 2004, Liver 53:392-400; Tsutsui et al., 2000, Immunological Reviews 174:192-209; Ludwiczek et al., 2002, J. Clinical Immunology 22:331-337), pancreatic diseases, and cardiovascular diseases (Gerdes et al, 2002, J. Exp. Med. 195:245-257; WO03/080104; WO02/060479; WO01/85201; Raeburn et al., 2002, Am. J. Physiol. Heart Circ. Physiol. 283:H650-H657). Accordingly, it is desirable to generate new agents capable of modulating the IL-18/IL-18 receptor interaction.